This program is concerned with understanding visual processing in the mammalian retina with an emphasis on inner retina cellular and circuitry organization, and the functional role of its amacrine cell populations in visual information processing. The focus of this application is on a novel amacrine cell population containing vasoactive intestinal polypeptide (VIP) and GABA immunoreactivity. Our studies show an unexpected complexity in the cellular organization and physiological properties of this cell population, which includes two major VIP amacrine cell types, complex intrinsic properties and regulation of the receptive field properties of ON ganglion cells. These findings indicate an action of the VIP amacrine cell population on distinct inner retinal cell circuits. We aim to establish the cellular features and connectivity of this novel amacrine cell population, and delineate its regulation of ganglion cell receptive field properties. Proposed studies will test th hypothesis that VIP amacrine cell subtypes form distinct inner retinal microcircuits and provide inhibitory GABA-mediated inputs and VIP-mediated extrasynaptic influences that regulate ganglion cell responses. We will test this idea as follows. Specific Aim 1: Establish the cellular and population attributes, and functional properties of VIP amacrine cells. Experiments will determine A) the subtype morphology and distribution, B) intrinsic electrophysiological and C) light-evoked properties of the VIP amacrine cell population. Specific Aim 2: Determine the microcircuit partners of VIP amacrine cells with bipolar, ganglion and other amacrine cells by delineating their A) synaptic and B) gap junction connectivity, and C) extrasynaptic VIP receptor sites. Specific Aim 3: Test the VIP amacrine cell population regulation of ganglion cell responses. Experiments will A) investigate and optimize the orthogonal chemogenetic (PSAM and DREADD) silencing of VIP amacrine cells to inhibit the VIP amacrine cell network, B) determine changes to ganglion cell receptive field properties induced by chemogenetic silencing of the VIP amacrine cell network, and C) discriminate the inhibitory actions of GABA and VIP released from the VIP amacrine cell population. Experimental studies will use transgenic mouse lines, immunohistochemistry, confocal and multiphoton microscopy, patch-clamp electrophysiology and multielectrode array recordings with chemogenetic silencing of the VIP amacrine cell network. Proposed studies will further the understanding of the functional role of the VIP amacrine cell population in the retina, and they will provide the basis for a better understanding of visual information processing by the retina. These objectives are consistent with the health-related goals of the National Eye Institute for the development of therapeutic approaches for the treatment and prevention of retinal disease.